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Stereoselective Glycal Fluorophosphorylation: Synthesis of ADP‐2‐fluoroheptose, an Inhibitor of the LPS Biosynthesis
Author(s) -
Dohi Hirofumi,
Périon Régis,
Durka Maxime,
Bosco Michael,
Roué Yvain,
Moreau François,
Grizot Sylvestre,
Ducruix Arnaud,
Escaich Sonia,
Vincent Stéphane P.
Publication year - 2008
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200801279
Subject(s) - selectfluor , stereoselectivity , chemistry , trifluoromethanesulfonate , glycal , stereochemistry , biosynthesis , heptose , electrophile , fluorine , octane , combinatorial chemistry , reagent , organic chemistry , enzyme , biochemistry , catalysis , gene , mutant
Abstract Heptosides are found in important bacterial glycolipids such as lipopolysaccharide (LPS), the biosynthesis of which is targeted for the development of novel antibacterial agents. This work describes the synthesis of a fluorinated analogue of ADP‐ L ‐ glycero ‐β‐ D ‐ manno ‐heptopyranose, the donor substrate of the heptosyl transferase WaaC, which catalyzes the incorporation of this carbohydrate into LPS. Synthetically, the key step for the preparation of ADP‐2F‐heptose is the simultaneous and stereoselective installation of both the fluorine atom at C‐2 and the phosphoryl group at C‐1 through a selectfluor‐mediated (selectfluor=1‐chloromethyl‐4‐fluorodiazoniabicyclo[2.2.2]octane bis(triflate)) electrophilic addition/nucleophilic substitution involving a heptosylglycal. Therefore, we detail in this article 1) the stereoselective preparation of the key intermediates heptosylglycals, 2) the development of a new fluorophosphorylation procedure allowing an excellent β‐ gluco stereoselectivity with “all‐equatorial” glycals, 3) the synthesis of the target ADP‐2F‐heptose, and 4) some comments on the contacts observed between the fluorine atom of the final molecule and the protein in the crystallographic structure of heptosyltransferase WaaC.